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Biomedical subjects

M A Kirschner

Publications and source records attributed to M A Kirschner.

At least 37 records · Page 2Linked to original sources
PubMed1987

Clinical usefulness of plasma androstanediol glucuronide measurements in women with idiopathic hirsutism.

Serum androstanediol glucuronide (3 alpha-diol G), a metabolite of the active androgens dihydrotestosterone and androstanediol, was elevated in 28 consecutive women with idiopathic hirsutism (IH). The mean 3 alpha-diol G level in the women with IH was 487 +/- 192 (+/- SD) ng/dL compared to 119 +/- 37 ng/dL in normal women (n = 50), and only 1 patient had a value overlapping with the normal range. Since 3 alpha-diol G appears to be formed entirely in target organs and has a long serum half-life, we studied its clinical usefulness by following women with IH during treatment. In 15 of 17 women with IH treated for 1-4 yr with glucocorticoids, contraceptives, or spironolactone, serum 3 alpha-diol G levels changed concordantly with clinical responses, in contrast to the poor concordance of serum testosterone (5 of 17), free testosterone (7 of 17), and androstenedione (7 of 17). Specifically, in IH patients treated with spironolactone, serum testosterone, free testosterone, and androstenedione levels changed little, yet clinical improvement frequently occurred, and this improvement was reflected by concomitantly lowered 3 alpha-diol G levels. Further, in 4 IH patients, discontinuation of effective therapy resulted in prompt increases in serum 3 alpha-diol G as harbingers of worsening hair growth. We, thus, conclude that serum 3 alpha-diol G measurements are clinically useful in evaluating hirsute women and correlate with the clinical responses to therapy.

Adolescent↗
PubMed1986

Endocrine impact of pure estradiol replacement in postmenopausal women: alterations in anterior pituitary hormone release and circulating sex steroid hormone concentrations.

Thirteen healthy postmenopausal volunteers were studied under basal conditions and at intervals (days 1, 5, 10, and 30) after intravaginal placement of a polysiloxane ring impregnated with 400 mg of estradiol. Mean serum estradiol concentrations rose 26-fold with a twofold increase in serum estrone concentrations. Serum delta 4-androstenedione, dehydroepiandrosterone sulfate, and total testosterone did not change, but absolute and percent free testosterone concentrations declined significantly by day 5. Concurrently, serum concentrations of immunoactive follicle-stimulating hormone declined progressively, while serum luteinizing hormone and free alpha-subunit concentrations exhibited a biphasic pattern of suppression. Serum levels of prolactin increased monophasically and those of growth hormone, somatomedin C, and thyroid-stimulating hormone did not change.

Estradiol↗
PubMed1984

Elevated production and metabolic clearance rates of androgens in morbidly obese women.

Blood production rates of testosterone, dihydrotestosterone (DHT), and 3 alpha-androstanediol (3 alpha-diol) were found to be approximately 2-fold elevated in morbidly obese, nonhirsute, normally menstruating women. Values were intermediate between those found in normal women and those in a group of nonobese normally menstruating women with idiopathic hirsutism. Elevated androgen production rates in obese women were associated with 2- to 3-fold increases in MCRs, presumably due to decreased levels of sex hormone-binding globulin. Thus, increased production rates were offset by increased MCRs, resulting in plasma testosterone, DHT, and 3 alpha-diol concentrations that were similar in the obese and normal women. By contrast, women with hirsutism had increased production rates associated with elevated plasma androgens as well as increased MCRs. Urinary excretion of testosterone glucuronide and 3 alpha-diol glucuronide (3 alpha-diol G) were elevated in both obese and hirsute women, paralleling the increased androgen production rates. Despite increased production rates and excretion of androgens, obese women exhibited no menstrual abnormalities, hirsutism, or other signs of virilism. To explore the apparent ineffectiveness of increased androgen production to produce virilizing symptoms, we measured plasma 3 alpha-diol G levels as a measure of peripheral androgen action. The mean +/- SE plasma 3 alpha-diol G was 53 +/- 8 ng/dl in obese women and 36 +/- 6 in normal women; by contrast, women with idiopathic hirsutism had levels of 440 +/- 99, a 12-fold elevation. Plasma testosterone glucuronide in obese and hirsute women were only 2- to 3-fold elevated, while plasma DHT glucuronide was not increased in obese women and was only 2-fold elevated in hirsute women. Thus, obesity is a state of increased androgen production and accelerated clearance. 3 alpha-diol G levels in obese women were only minimally elevated, in contrast to values in the hirsute women, perhaps reflecting the apparent androgen ineffectiveness.

Adult↗
PubMed1984

Hirsutism and virilism in women.

Hirsutism in women may be defined as excessive thick (terminal) hair growth in facial and body regions. It is one of the early manifestations of virilization that correlate closely with elevated testosterone production. Testosterone production rates in normal women average 0.2 mg/day, with 25% secreted by the ovaries, 25% by the adrenals, and 50% arising from the peripheral metabolism of prehormones, notably androstenedione. Increased testosterone from adrenal and/or ovarian sources induces 5 alpha-reductase activity within the susceptible hair follicle. This results in the local production of dihydrotestosterone, the potent androgen that is likely responsible for the growth and stimulation of the hair follicle that leads to hirsutism. Activation of the hair follicle by androgens provides a secondary pathway for testosterone metabolism, unfortunately at the expense of undesirable hair growth. Although virilization in women may be caused by exogenous androgens, it occurs primarily from diseases of the adrenals or ovaries. Androgen-producing tumors of the adrenals cause virilization in association with excessive production of a wide variety of C19 androgens. In contrast, ovarian tumors tend to secrete a narrower range of androgens and their presence may be more occult. The most common causes of hirsutism in women arise from nontumorous states, chiefly ovarian in origin. The androgenized ovary syndrome represents a spectrum of abnormalities ranging from idiopathic hirsutism to the polycystic ovary syndrome to ovarian hyperthecosis. These states are associated with mild to severe abnormalities of androgen production and concomitant mild to severe abnormalities of ovarian histology. The pathogenesis of these abnormalities is still speculative, but appears to be related to increased pulsatile and tonic secretion of LH with ovarian hyperstimulation. Of the various laboratory tests to evaluate hirsutism, simple measurements of plasma testosterone, free testosterone, and most recently androstanediol glucuronide seem to provide the best chemical evidence of androgen abnormalities. Treatment of hirsutism/virilism in women is difficult and frequently unsatisfactory. At present, treatment schemes include local methods, suppression of androgens via glucocorticoids or oral contraceptives, and antiandrogens.

Adrenal Cortex Neoplasms↗
PubMed1983

A comparison of androgen production and clearance in hirsute and obese women.

Virilization in women is associated with increased production of testosterone as well as a variety of androgenic prehormones, including androstenedione, androstenediol, DHEA, DHEA-sulfate, dihydrotestosterone and androstanediol. Of these hormones, it is likely that testosterone is the androgen which initiates a series of androgen-receptor mediated events resulting in stimulation of 5 alpha reductase in the skin and hair follicles, producing dihydrotestosterone locally. The metabolism of testosterone to dihydrotestosterone within the hair follicle results in increased clearance of testosterone, however at the expense of hair follicle stimulation. Increased 5 alpha reductase of the skin and hair allows other prehormones to be metabolized to dihydrotestosterone and androstanediol, further stimulating the hair follicle (multiplier effect). In obese women, androgen production rates are elevated and SHBG levels are depressed, in many cases to the same magnitude as that observed in hirsute women. Increased androgen production rates in obesity, however, are associated with major increases in clearance rates of these androgens. Resultant androgen blood levels are even lower than observed in the non-obese population. It appears likely that adipose tissue is the site of the increased clearance rates and metabolism of prehormones to dihydrotestosterone and androstanediol. A delicate balance likely exists between production and clearance of these biologically active hormones. Minor aberrations in this balance may result in the increased incidence of hirsutism seen in the obese female population.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1983

Therapeutic effects of spironolactone in polycystic ovary syndrome.

The authors examined the effect of three months' treatment with spironolactone in 34 women with polycystic ovary syndrome. In all patients a significant decrease in hirsutism was noted as well as restoration of a regular although anovulatory menstrual pattern. Plasma luteinizing hormone and follicle-stimulating hormone levels remained unchanged after spironolactone treatment; however, prolactin levels were lowered in both women with normal and those with elevated basal levels. Plasma testosterone, androstenedione, and dehydroepiandrosterone sulfate levels were decreased after three months of therapy. No side effects were observed. Plasma electrolytes and liver function tests were normal during the entire time of treatment. This therapy is recommended as initial nontoxic but effective treatment for women with polycystic ovary syndrome who are hirsute and have menstrual disturbances.

Adult↗
PubMed1982

Steroid hormone profiles in women treated with aminoglutethimide for metastatic carcinoma of the breast.

Recent evidence suggests that aminoglutethimide (AG), a known inhibitor of adrenal steroidogenesis, is a potent blocker of aromatase and thus of estrogen production. These properties of AG have been exploited clinically to reduce the biosynthesis of adrenal estrogen precursors and extraglandular estrogen production in postmenopausal women with metastatic breast carcinoma. In this study, we have explored the effects of AG on a variety of steroids, including delta 5-C19 and -C21 compounds and delta 4-C19 and -C21 steroids as well as plasma and urinary estrogens in a series of postmenopausal women with breast cancer treated for 2 to 26 weeks. Plasma concentrations of delta 5-C21 and -C19 compounds were reduced 3- to 5-fold during AG therapy and remained suppressed over the duration of the study. By contrast, the delta 4-steroids such as progesterone, androstenedione, and 17 alpha- hydroxyprogesterone rose 2- to 10-fold during the initial 2 weeks of AG treatment and then fell back to starting levels or were suppressed. Plasma levels of the potent androgens testosterone and dihydrotestosterone were relatively preserved during AG therapy. The possible contribution of the postmenopausal ovary to the above hormone levels during AG therapy was examined by comparing steroid values from surgically castrated and spontaneously menopausal women. No statistically significant differences between the two groups were observed. In response to AG therapy, plasma levels of estrone and estrone sulfate were decreased 61 to 72%, and urinary estrone similarly fell 85% over the 12-week period. Estradiol concentrations in urine and plasma were similarly reduced 40 to 66% from basal values over this same period.

Adrenal Glands↗
PubMed1981

Estrogen production as a tumor marker in patients with gonadotropin-producing neoplasms.

Urinary estradiol production rates, plasma estradiol, and peripheral conversion of dehydroepiandrosterone sulfate (DHEAS) to estradiol were explored in patients whose neoplasms made human chorionic gonadotropin and/or human chorionic gonadotropin beta fragments. In five men with choriocarcinoma, estradiol production was elevated, plasma estradiol was high, and DHEAS conversion to estradiol ranged from 0.5 to 11.7%. In six patients with "ectopic" gonadotropin-producing tumors, originating from lung, stomach, and liver, estradiol production was elevated to a lesser degree. Sera from 154 of 864 patients (16.8%) with a wide variety of advanced neoplastic disorders were noted to have minimal elevations of human chorionic gonadotropin beta subunit in their sera but had normal luteinizing hormone assays. Plasma estradiol levels in these patients were not elevated, and in only one of ten patients studied was there slight elevation of the estradiol production rate. Similarly, in only one of ten patients was there measurable conversion of DHEAS to estradiol. We conclude that, in patients whose neoplastic disorders are associated with major elevations of human chorionic gonadotropin, there is concordant extragonadal production of estradiol via DHEAS, presumably representing an associated trophoblastic function. However, estrogen production is not a sensitive tumor marker in those patients whose neoplasms are associated with minimal elevations of human chorionic gonadotropin beta fragments only.

Choriocarcinoma↗
PubMed1981

Obesity, hormones, and cancer.

Obesity is a physiological state associated with alterations in hormone production and metabolism. These hormonal changes may bear on the increased risk for selected neoplastic disorders. Obesity is associated with increased estrone production in young and older women as well as in men. The source of this increased estrogen appears to be extragonadal metabolism of the prehormone androstenedione, which increases 3- to 4-fold in proportion to the obesity. In severe obesity, androstenedione production itself may be increased, providing extra prehormone for conversion to estrogens. In addition, obesity appears to shift peripheral metabolism of estradiol, resulting in decreased excretion of catechol estrogens which in turn may influence target organ stimulation. Testosterone production is unchanged in obesity; however, there are decreased levels of sex hormone-binding beta-globulin leading to increased clearance rates and spuriously low levels of circulating testosterone in both obese men and obese women. Alterations in sex hormone-binding beta-globulin may further lead to changes in "free" estradiol, which may play a role in target organ stimulation. Other changes noted in obesity include: (a) increased excretion of corticoid metabolites; (b) increased secretion of insulin but decreased insulin effectiveness; (c) blunted growth hormone responses to various challenges; and (d) possibly blunted prolactin responsiveness. There are no reasons at present to suspect that these changes influence cancer risk. With weight loss, sex hormone-binding beta-globulin changes are restored toward normal as are the elevated plasma estrogens and decreased testosterone levels. BEcause weight loss and dieting per se are associated with many physiological changes, hormonal measurements during these times are difficult to interpret. Few studies to date have been performed in formerly obese patients stabilized at their new weight.

Androgens↗
PubMed1979

Increased estrogen production in obese men.

Serum estrone (E1) and 17beta-estradiol (E2) were noted to be 2-fold elevated in a group of morbidly obese men. Urinary E1 and E2 production rates were elevated in proportion to the degree of obesity, with values as high as 127 and 157 micrograms/day, respectively. Although serum testosterone (T) concentrations were reduced in obese men, averaging 348 +/- 35 vs. 519 +/- 42 ng/dl in lean controls, the dialyzable T fractions were elevated and, hence, the calculated free T concentrations were normal in obese men. Further, the obese men exhibited normal serum LH, FSH, and T responses to clomiphene citrate, indicating intact hypothalamic-pituitary-Leydig cell axes. MCRs of T and peripheral conversion of T to E2 and androstenedione (delta) to E1 were all increased in obese men in proportion to the percentage above ideal weight. Although the obese mean exhibited increased blood levels and production rates of estrogens, there were no signs of feminization, increased T-estrogen-binding, globulin levels, or suppressed basal gonadotropin levels, suggesting a lack of biological effect. We postulate that obese men exhibit defective estrogen receptors, leading to decreased T-estrogen-binding globulin, increased clearance of androgenic hormones, and elevated estrogen production rates.

Body Weight↗
PubMed1977

Mechanism of feminization in primary liver cancer.

Primary liver cancer occasionally presents with feminization. The mechanism is unknown. We studied a young man with primary liver cancer associated with feminization that disappeared after removal of the tumor. Before operation, the serum estrone level was markedly (1113 pg per milliliter) and estradiol and estriol levels were slightly elevated. Human placental lactogen was also increased (0.52 microng per milliliter). Luteinizing hormone, follicle-stimulating hormone and prolactin levels were normal, and testosterone reduced. Beta subunits of human chorionic gonadotropin were not detected in the serum. In vitro assay of tumor tissue showed estrogenic activity and high levels of these subunits. With a reversed isotope dilution technic with crystallization to constant specific activity, we showed the tumor tissue to convert dehydroepiandrosterone sulfate and dehydroepiandrosterone to estrone and estradiol. Production of beta subunits of chorionic gonadotropin and raised serum levels of placental lactogen provided further evidence that the tumor was functioning as trophoblastic tissue.

Adult↗
PubMed1976

Idiopathic hirsutism--an ovarian abnormality.

We investigated increased production of testosterone and androstenedione in 44 women with unexplained adult-onset hirsutism, 41 of whom had normal-sized ovaries. Twenty women in this group had at least 50 per cent suppression of plasma testosterone and androstenedione after four to five days of dexamethasone. Testosterone and androstenedione values in ovarian-vein effluents were higher than those of their adrenal veins. We calculated adrenal secretion rates of both androgens in each patient by relating the adrenal gradients to those of cortisol. In 42 of the hirsute women, including those whose androgens were suppressed after dexamethasone, the ovaries were the predominant source of androgen production. The women with dexamethasone suppression had milder degrees of virilism and lower production rates of testosterone and androstenedione. We conclude that the ovaries are the source of excessive androgens in most women with unexplained hirsutism, and that corticoid-suppressible patients have milder forms of ovarian hyperandrogenism.

Adrenal Glands↗
PubMed1976

Concurrence of aldosterone, androgen, and cortisol secretion in adrenal venous effluents.

Adrenal effluent concentrations of aldosterone were measured along with testosterone, androstenedione, and cortisol in 17 women with idiopathic hirsutism. In the basal state, aldosterone secretion (higher concentrations vs peripheral blood) was demonstrated in 14 out of 16 of the women, in contrast to 8 out of 16 who demonstrated cortisol gradients. Nine women received 0.25 mgm beta 1-24 ACTH im and serial adrenal venous blood samples were obtained over the next 30 minutes. Parallel 30-40-fold increments were noted in aldosterone, androstenedione, and cortisol; testosterone increased only 8-fold. These marked changes in adrenal effluents were not observed in simultaneously monitored peripheral blood. Minimal changes in these steroid concentrations were noted in adrenal and peripheral blood in 7 women who received 2,000 IU hCG. One woman received a pressor dose of angiotensin II, resulting in a marked increase in adrenal vein aldosterone and a simultaneous decrease in cortisol. Since adrenal androgen secretion parallels cortisol, quantification of adrenal androgen secretion rates can be achieved by sampling the adrenal effluent and relating the androgen gradient to that of cortisol at any given time. In contrast, aldosterone secretion is often independent of cortisol, and thus cannot be estimated by comparison of adrenal gradients. ACTH administration, however, invariably stimulated aldosterone secretion, enabling us to quantify the "ACTH-related aldosterone secretion rate" from a comparison of maximal adrenal gradients of aldosterone vs cortisol. In 6 women, "ACTH-related aldosterone" secretion rate averaged 40 mug/day, roughly 20% of the total daily aldosterone secretion rate.

Adrenal Glands↗